Ethyl 2-substituted-1-(substitutedbenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate derivatives as anti-tubercular agents

ABSTRACT

Compounds for treating tuberculosis and, particularly, anti-tubercular compounds that are ethyl 2-substituted-1-(substitutedbenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate derivatives and their use as anti-tubercular agents are provided.

BACKGROUND 1. Field

The present disclosure relates to compounds for treating tuberculosisand, particularly, to anti-tubercular compounds that are ethyl2-substituted-1-(substitutedbenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylatederivatives and their use as anti-tubercular agents, including asanti-tubercular agents against MDR strains of Mycobacteriumtuberculosis.

2. Description of the Related Art

Tuberculosis (TB) is a communicable infectious disease and a major causeof illness, particularly in low-income countries. It is caused by theopportunistic bacillus Mycobacterium tuberculosis (MTB), which primarilyattacks the lungs (pulmonary), but may later affect other parts(extra-pulmonary) of the body. Several factors have contributed to thecontinuous health threat of TB globally, including the development ofdrug resistance, such as multidrug-resistant tuberculosis (MDR-TB),extensively drug-resistant tuberculosis (XDR-TB), and totallydrug-resistant tuberculosis (TDR-TB); the co-morbidities with acquiredimmunodeficiency syndrome (AIDS), and the risks involved in developingdiabetes mellitus among TB patients. New therapeutic strategies areneeded to combat the tuberculosis pandemic and the growing resistance toconventional anti-TB drugs, which remain a serious public healthchallenge worldwide.

In the past forty years, very few new anti-tubercular (anti-TB) drugshave been approved, with the exception of Bedaquiline (Approved in 2012by the US-FDA), Delamanid (Approved in 2014 in Europe), and Pretomanid(Approved in 2019 by the US-FDA). As these drugs are typically noteffective by themselves, they are usually combined with first-line andsecond-line anti-TB drugs. These conventional anti-TB drugs areassociated with significant side effects. Further, clinical resistanceto conventional anti-TB drugs has been widely reported in extensivelydrug-resistant tuberculosis (XDR-TB) patients.

Thus, anti-tubercular compounds solving the aforementioned problems aredesired.

SUMMARY

In the process of discovering a novel anti-tubercular (anti-TB agent)with a new molecular mechanism of action, a series of ethyl2-substituted-1-(substitutedbenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylatederivatives has been developed by a synthetic chemical method andpurified by a column chromatographic method. Structural elucidation ofthe compounds has been completed by spectral techniques such as FT-IR,NMR (¹H and ¹³C), and HRMS. These compounds have been found to possessanti-TB activity against H37Rv and, multi-drug resistance (MDR) strainsof Mycobacterium tuberculosis. Some compounds show promisinganti-tubercular activity at millimolar to micromolar concentrations whentested alone against whole-cell Mycobacterium tuberculosis organisms.

In an embodiment, the present subject matter relates to a compoundhaving the formula I:

or a pharmaceutically acceptable salt, ester, stereoisomer, or solvatethereof, wherein:

-   -   R is selected from the group consisting of methyl, hydrogen,        fluorine, bromine, —NO₂, and trifluoromethyl; and    -   n is 1 or 2.

In another embodiment, the present subject matter relates to a method oftreating tuberculosis in a patient, comprising administering to apatient in need thereof a therapeutically effective amount of a compoundhaving the formula I:

or a pharmaceutically acceptable salt, ester, stereoisomer, or solvatethereof, wherein:

-   -   R is selected from the group consisting of methyl, hydrogen,        fluorine, bromine, —NO₂, and trifluoromethyl; and    -   n is 1 or 2.

In a further embodiment, the present subject matter relates to acompound having the formula I:

or a pharmaceutically acceptable salt, ester, stereoisomer, or solvatethereof, wherein:

-   -   R is selected from the group consisting of methyl, fluorine, and        trifluoromethyl; and    -   n is 1 or 2.

In another embodiment, the present subject matter relates to a method oftreating tuberculosis in a patient, comprising administering to apatient in need thereof a therapeutically effective amount of a compoundhaving the formula I:

or a pharmaceutically acceptable salt, ester, stereoisomer, or solvatethereof, wherein:

-   -   R is selected from the group consisting of methyl, fluorine, and        trifluoromethyl; and    -   n is 1 or 2.

In a further embodiment, the present subject matter relates to acompound selected from the group consisting of: Ethyl7-methyl-1-(4-methylbenzoyl)pyrrolo[1,2-a]quinoline-3-carboxylate (4a);Ethyl 1-benzoyl-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate (4b);Ethyl 1-(4-fluorobenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4c); Ethyl7-methyl-1-(2-nitrobenzoyl)pyrrolo[1,2-a]quinoline-3-carboxylate (4d);Ethyl 1-(4-bromobenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4e); Ethyl1-(3,5-bis(trifluoromethyl)benzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4f) and a pharmaceutically acceptable salt, ester, stereoisomer, orsolvate thereof.

In a further embodiment, the present subject matter relates to acompound selected from the group consisting of: Ethyl7-methyl-1-(4-methylbenzoyl)pyrrolo[1,2-a]quinoline-3-carboxylate (4a);Ethyl 1-(4-fluorobenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4c); Ethyl1-(3,5-bis(trifluoromethyl)benzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4f) and a pharmaceutically acceptable salt, ester, stereoisomer, orsolvate thereof.

In yet another embodiment, the present subject matter relates to amethod of treating tuberculosis in a patient, comprising administeringto a patient in need thereof a therapeutically effective amount of acompound selected from the group consisting of: Ethyl7-methyl-1-(4-methylbenzoyl)pyrrolo[1,2-a]quinoline-3-carboxylate (4a);Ethyl 1-benzoyl-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate (4b);Ethyl 1-(4-fluorobenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4c); Ethyl7-methyl-1-(2-nitrobenzoyl)pyrrolo[1,2-a]quinoline-3-carboxylate (4d);Ethyl 1-(4-bromobenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4e); Ethyl1-(3,5-bis(trifluoromethyl)benzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4f) and a pharmaceutically acceptable salt, ester, stereoisomer, orsolvate thereof.

In still yet another embodiment, the present subject matter relates to amethod of treating tuberculosis in a patient, comprising administeringto a patient in need thereof a therapeutically effective amount of acompound selected from the group consisting of: Ethyl7-methyl-1-(4-methylbenzoyl)pyrrolo[1,2-a]quinoline-3-carboxylate (4a);Ethyl 1-(4-fluorobenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4c); Ethyl1-(3,5-bis(trifluoromethyl)benzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4f); and a pharmaceutically acceptable salt, ester, stereoisomer, orsolvate thereof.

In another embodiment, the present subject matter relates to a method oftreating tuberculosis in a patient, comprising administering to apatient in need thereof a therapeutically effective amount of a compoundselected from the group consisting of: Ethyl7-methyl-1-(2-nitrobenzoyl)pyrrolo[1,2-a]quinoline-3-carboxylate (4d);Ethyl 1-(4-bromobenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4e); Ethyl1-(3,5-bis(trifluoromethyl)benzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4f); and a pharmaceutically acceptable salt, ester, stereoisomer, orsolvate thereof.

In an embodiment, the present subject matter relates to a process forthe synthesis of the compounds of formula I, including a number ofspecies or specific structures falling under structural formula I.Further contemplated herein are pharmaceutical compositions containingthese compounds, as well as methods of treating tuberculosis byadministering the present compounds to a patient in need thereof.

These and other features of the present subject matter will becomereadily apparent upon further review of the following specification.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following definitions are provided for the purpose of understandingthe present subject matter and for construing the appended patentclaims.

Definitions

Throughout the application, where compositions are described as having,including, or comprising specific components, or where processes aredescribed as having, including, or comprising specific process steps, itis contemplated that compositions of the present teachings can alsoconsist essentially of, or consist of, the recited components, and thatthe processes of the present teachings can also consist essentially of,or consist of, the recited process steps.

It is noted that, as used in this specification and the appended claims,the singular forms “a”, “an”, and “the” include plural references unlessthe context clearly dictates otherwise.

In the application, where an element or component is said to be includedin and/or selected from a list of recited elements or components, itshould be understood that the element or component can be any one of therecited elements or components, or the element or component can beselected from a group consisting of two or more of the recited elementsor components. Further, it should be understood that elements and/orfeatures of a composition or a method described herein can be combinedin a variety of ways without departing from the spirit and scope of thepresent teachings, whether explicit or implicit herein.

The use of the terms “include,” “includes”, “including,” “have,” “has,”or “having” should be generally understood as open-ended andnon-limiting unless specifically stated otherwise.

The use of the singular herein includes the plural (and vice versa)unless specifically stated otherwise. In addition, where the use of theterm “about” is before a quantitative value, the present teachings alsoinclude the specific quantitative value itself, unless specificallystated otherwise. As used herein, the term “about” refers to a ±10%variation from the nominal value unless otherwise indicated or inferred.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo, andiodo.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not.

It will be understood by those skilled in the art with respect to anychemical group containing one or more substituents that such groups arenot intended to introduce any substitution or substitution patterns thatare sterically impractical and/or physically non-feasible.

The term “isomers” or “stereoisomers” as used herein relates tocompounds that have identical molecular formulae but that differ in thearrangement of their atoms in space. Stereoisomers that are not mirrorimages of one another are termed “diastereoisomers” and stereoisomersthat are non-superimposable mirror images are termed “enantiomers,” orsometimes optical isomers. A carbon atom bonded to four non-identicalsubstituents is termed a “chiral center.” Certain compounds herein haveone or more chiral centers and therefore may exist as either individualstereoisomers or as a mixture of stereoisomers. Configurations ofstereoisomers that owe their existence to hindered rotation about doublebonds are differentiated by their prefixes cis and trans (or Z and E),which indicate that the groups are on the same side (cis or Z) or onopposite sides (trans or E) of the double bond in the molecule accordingto the Cahn-Ingold-Prelog rules. All possible stereoisomers arecontemplated herein as individual stereoisomers or as a mixture ofstereoisomers.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood to one of ordinary skill inthe art to which the presently described subject matter pertains.

Where a range of values is provided, for example, concentration ranges,percentage ranges, or ratio ranges, it is understood that eachintervening value, to the tenth of the unit of the lower limit, unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the described subject matter. Theupper and lower limits of these smaller ranges may independently beincluded in the smaller ranges, and such embodiments are alsoencompassed within the described subject matter, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both of the limits, ranges excluding either or both ofthose included limits are also included in the described subject matter.

Throughout the application, descriptions of various embodiments use“comprising” language. However, it will be understood by one of skill inthe art, that in some specific instances, an embodiment canalternatively be described using the language “consisting essentiallyof” or “consisting of”.

“Subject” as used herein refers to any animal classified as a mammal,including humans, domestic and farm animals, and zoo, sports, and petcompanion animals such as household pets and other domesticated animalssuch as, but not limited to, cattle, sheep, ferrets, swine, horses,poultry, rabbits, goats, dogs, cats and the like.

“Patient” as used herein refers to a subject in need of treatment of acondition, disorder, or disease, such as an acute or chronic airwaydisorder or disease.

For purposes of better understanding the present teachings and in no waylimiting the scope of the teachings, unless otherwise indicated, allnumbers expressing quantities, percentages or proportions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about”.Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, each numerical parametershould at least be construed in light of the number of reportedsignificant digits and by applying ordinary rounding techniques.

In an embodiment, the present subject matter relates to a compoundhaving the formula I:

or a pharmaceutically acceptable salt, ester, stereoisomer, or solvatethereof, wherein:

-   -   R is selected from the group consisting of methyl, hydrogen,        fluorine, bromine, —NO₂, and trifluoromethyl; and    -   n is 1 or 2.

In one embodiment, R and n, when taken together, can be selected fromthe group consisting of 4-methyl, 4-hydrogen, 4-bromine, 4-fluorine,2-nitro, and 3,5-CF₃.

In a further embodiment, the present subject matter relates to acompound having the formula I:

or a pharmaceutically acceptable salt, ester, stereoisomer, or solvatethereof, wherein:

-   -   R is selected from the group consisting of methyl, fluorine, and        trifluoromethyl; and    -   n is 1 or 2.

In one embodiment, R and n, when taken together, can be selected fromthe group consisting of 4-methyl, 4-fluorine, and 3,5-CF₃.

In a further embodiment, the present subject matter relates to acompound selected from the group consisting of: Ethyl7-methyl-1-(4-methylbenzoyl) pyrrolo[1,2-a]quinoline-3-carboxylate (4a);Ethyl 1-benzoyl-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate (4b);Ethyl 1-(4-fluorobenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4c); Ethyl7-methyl-1-(2-nitrobenzoyl)pyrrolo[1,2-a]quinoline-3-carboxylate (4d);Ethyl 1-(4-bromobenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4e); Ethyl1-(3,5-bis(trifluoromethyl)benzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4f); and a pharmaceutically acceptable salt, ester, stereoisomer, orsolvate thereof.

In certain embodiments, the present subject matter relates to a compoundselected from the group consisting of: Ethyl7-methyl-1-(4-methylbenzoyl)pyrrolo[1,2-a]quinoline-3-carboxylate (4a);Ethyl 1-(4-fluorobenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4c); Ethyl1-(3,5-bis(trifluoromethyl)benzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4f); and a pharmaceutically acceptable salt, ester, stereoisomer, orsolvate thereof.

In another embodiment, the present subject matter relates to a method oftreating tuberculosis in a patient, comprising administering to apatient in need thereof a therapeutically effective amount of a compoundhaving the formula I:

or a pharmaceutically acceptable salt, ester, stereoisomer, or solvatethereof, wherein:

-   -   R is selected from the group consisting of methyl, hydrogen,        fluorine, bromine, —NO₂, and trifluoromethyl; and    -   n is 1 or 2.

In one embodiment of the compounds used in the present methods, R and n,when taken together, can be selected from the group consisting of4-methyl, 4-hydrogen, 4-bromine, 4-fluorine, 2-nitro, and 3,5-CF₃.

In another embodiment, the present subject matter relates to a method oftreating tuberculosis in a patient, comprising administering to apatient in need thereof a therapeutically effective amount of a compoundhaving the formula I:

or a pharmaceutically acceptable salt, ester, stereoisomer, or solvatethereof, wherein:

-   -   R is selected from the group consisting of methyl, fluorine, and        trifluoromethyl; and    -   n is 1 or 2.

In one embodiment of the compounds used in the present methods, R and n,when taken together, can be selected from the group consisting of4-methyl, 4-fluorine, and 3,5-CF₃.

In yet another embodiment, the present subject matter relates to amethod of treating tuberculosis in a patient, comprising administeringto a patient in need thereof a therapeutically effective amount of acompound selected from the group consisting of: Ethyl7-methyl-1-(4-methylbenzoyl)pyrrolo[1,2-a]quinoline-3-carboxylate (4a);Ethyl 1-benzoyl-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate (4b);Ethyl 1-(4-fluorobenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4c); Ethyl7-methyl-1-(2-nitrobenzoyl)pyrrolo[1,2-a]quinoline-3-carboxylate (4d);Ethyl 1-(4-bromobenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4e); Ethyl1-(3,5-bis(trifluoromethyl)benzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4f); and a pharmaceutically acceptable salt, ester, stereoisomer, orsolvate thereof.

In still yet another embodiment, the present subject matter relates to amethod of treating tuberculosis in a patient, comprising administeringto a patient in need thereof a therapeutically effective amount of acompound selected from the group consisting of: Ethyl 7-methyl-1-(4-methylbenzoyl)pyrrolo[1,2 -a]quinoline-3 -carboxylate (4a); Ethyl1-(4-fluorobenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3 -carboxylate (4c);Ethyl 1-(3,5-bis(trifluoromethyl)benzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate (40 ; and a pharmaceutically acceptable salt, ester,stereoisomer, or solvate thereof.

In another embodiment, the present subject matter relates to a method oftreating tuberculosis in a patient, comprising administering to apatient in need thereof a therapeutically effective amount of a compoundselected from the group consisting of: Ethyl 7-methyl-1-(2-nitrobenzoyl)pyrrolo[1,2-a]quinoline-3 -carboxylate (4d); Ethyl 1-(4-bromobenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate (4e);Ethyl 1-(3,5-bis(trifluoromethyl)benzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate (40 ; and a pharmaceutically acceptable salt, ester,stereoisomer, or solvate thereof.

Said differently, the present subject matter can relate to compounds offormula I and to methods of treating tuberculosis using compounds offormula I, i.e., ethyl2-substituted-1-(substitutedbenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylatederivatives, or pharmaceutically acceptable salts, esters,stereoisomers, or solvates thereof, having the following formulae:

It is to be understood that the present subject matter covers allcombinations of substituent groups referred to herein.

The present compounds may contain, e.g., when isolated in crystallineform, varying amounts of solvents. Accordingly, the present subjectmatter includes methods of using all solvates of the present compoundsof formula I and pharmaceutically acceptable stereoisomers, esters,and/or salts thereof. Hydrates are one example of such solvates.

Further, the present subject matter includes methods of using allmixtures of possible stereoisomers of the embodied compounds,independent of the ratio, including the racemates.

Salts of the compounds, or salts of the stereoisomers thereof, includeall inorganic and organic acid addition salts and salts with bases,especially all pharmaceutically acceptable inorganic and organic acidaddition salts and salts with bases, particularly all pharmaceuticallyacceptable inorganic and organic acid addition salts and salts withbases customarily used in pharmacy.

Examples of acid addition salts include, but are not limited to,hydrochlorides, hydrobromides, phosphates, nitrates, sulfates, acetates,trifluoroacetates, citrates, D-gluconates, benzoates,2-(4-hydroxy-benzoyl)benzoates, butyrates, subsalicylates, maleates,laurates, malates, lactates, fumarates, succinates, oxalates, tartrates,stearates, benzenesulfonates (besilates), toluenesulfonates (tosilates),methanesulfonates (mesilates) and 3-hydroxy-2-naphthoates.

Examples of salts with bases include, but are not limited to, lithium,sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium,meglumine and guanidinium salts. The salts include water-insoluble and,particularly, water-soluble salts.

The present compounds, the salts, the stereoisomers and the salts of thestereoisomers thereof may contain, e.g., when isolated in crystallineform, varying amounts of solvents. Included within the present scopeare, therefore, all solvates of the compounds of formula I, as well asthe solvates of the salts, the stereoisomers and the salts of thestereoisomers of the compounds of formula I.

The present compounds may be isolated and purified in a manner known perse, e.g., by distilling off the solvent in vacuo and recrystallizing theresidue obtained from a suitable solvent or subjecting it to one of thecustomary purification methods, such as column chromatography on asuitable support material.

Salts of the compounds of formula I and the stereoisomers thereof can beobtained by dissolving the free compound in a suitable solvent (by wayof non-limiting example, a ketone such as acetone, methylethylketone ormethylisobutylketone; an ether such as diethyl ether, tetrahydrofuraneor dioxane; a chlorinated hydrocarbon such as methylene chloride orchloroform; a low molecular weight aliphatic alcohol such as methanol,ethanol or isopropanol; a low molecular weight aliphatic ester such asethyl acetate or isopropyl acetate; or water) which contains the desiredacid or base, or to which the desired acid or base is then added. Theacid or base can be employed in salt preparation, depending on whether amono- or polybasic acid or base is concerned and depending on which saltis desired, in an equimolar quantitative ratio or one differingtherefrom. The salts are obtained by filtering, reprecipitating,precipitating with a non-solvent for the salt or by evaporating thesolvent. Salts obtained can be converted into the free compounds which,in turn, can be converted into salts. In this manner, pharmaceuticallyunacceptable salts, which can be obtained, for example, as processproducts in the manufacturing on an industrial scale, can be convertedinto pharmaceutically acceptable salts by processes known to the personskilled in the art.

Pure diastereomers and pure enantiomers of the present compounds can beobtained, e.g., by asymmetric synthesis, by using chiral startingcompounds in synthesis and by splitting up enantiomeric anddiastereomeric mixtures obtained in synthesis. Preferably, the purediastereomeric and pure enantiomeric compounds are obtained by usingchiral starting compounds in synthesis.

Enantiomeric and diastereomeric mixtures can be split up into the pureenantiomers and pure diastereomers by methods known to a person skilledin the art. Preferably, diastereomeric mixtures are separated bycrystallization, in particular fractional crystallization, orchromatography. Enantiomeric mixtures can be separated, e.g., by formingdiastereomers with a chiral auxiliary agent, resolving the diastereomersobtained and removing the chiral auxiliary agent. As chiral auxiliaryagents, for example, chiral acids can be used to separate enantiomericbases and chiral bases can be used to separate enantiomeric acids viaformation of diastereomeric salts. Furthermore, diastereomericderivatives such as diastereomeric esters can be formed fromenantiomeric mixtures of alcohols or enantiomeric mixtures of acids,respectively, using chiral acids or chiral alcohols, respectively, aschiral auxiliary agents. Additionally, diastereomeric complexes ordiastereomeric clathrates may be used for separating enantiomericmixtures. Alternatively, enantiomeric mixtures can be split up usingchiral separating columns in chromatography. Another suitable method forthe isolation of enantiomers is enzymatic separation.

The present compounds can exhibit anti-TB activity against H37Rv andmultiple drug resistant (MDR) strains of Mycobacterium tuberculosis. Thecompounds can exhibit anti-TB properties at millimolar to micromolarconcentrations against whole cell Mycobacterium tuberculosis organisms.Accordingly, the anti-tubercular compounds can be effective agents fortreating tuberculosis.

In one embodiment, the compounds used in the present methods can beprepared according to the following general synthetic pathway as shownin Scheme 1.

In this regard, a synthetic scheme for the present compounds can includea one-pot synthesis by adding, to a stirred solution of6-methylquinoline (1), substituted phenacyl bromide (2), and K₂CO₃ inDMF, ethyl acetylenecarboxylate (3) with stirring. The reaction mixtureis stirred at room temperature for at least about 30 mins. Thecompletion of the reaction is monitored by TLC. The reaction mixture isevaporated under reduced pressure. The residue obtained is re-dissolvedin ethyl acetate, the ethyl acetate layer is washed with water, thenbrine, and dried with anhydrous sodium sulphate. The organic layer isevaporated under reduced pressure and purified to obtain 85-92% of ethyl1-substitutedbenzoyl-7-methylpyrrolo[1,2-a]quinoline-3-carboxylates(4a-f). The physicochemical properties of the title compounds aretabulated in Table 1.

TABLE 1 Physicochemical parameters of ethyl 2-substituted-1-(substitutedbenzoyl)-7-methylpyrrolo[1,2-a] quinoline-3-carboxylates(4a-f) Compound code Mol formulae R Yield (%)^(a) m.p (° C.) 4aC₂₄H₂₁NO₃ 4-CH₃ 86 155-156 4b C₂₃H₁₉NO₃ 4-H 89 139-140 4c C₂₃H₁₈FNO₃ 4-F90 163-164 4d C₂₃H₁₈N₂O₅ 2-NO₂ 92 174-175 4e C₂₃H₁₈BrNO₃ 4-Br 88 180-1814f C₂₅H₁₇F₆NO₃ 3,5-CF₃ 85 223-224 ^(a)Yields calculated afterpurification by column chromatography.

In another embodiment, the present subject matter is directed topharmaceutical compositions comprising a therapeutically effectiveamount of the compounds as described herein together with one or morepharmaceutically acceptable carriers, excipients, or vehicles. In someembodiments, the present compositions can be used for combinationtherapy, where other therapeutic and/or prophylactic ingredients can beincluded therein.

The present subject matter further relates to a pharmaceuticalcomposition, which comprises at least one of the present compoundstogether with at least one pharmaceutically acceptable auxiliary.

In an embodiment, the pharmaceutical composition comprises one or two ofthe present compounds, or one of the present compounds.

Non-limiting examples of suitable excipients, carriers, or vehiclesuseful herein include liquids such as water, saline, glycerol,polyethyleneglycol, hyaluronic acid, ethanol, and the like. Suitableexcipients for nonliquid formulations are also known to those of skillin the art. A thorough discussion of pharmaceutically acceptableexcipients and salts useful herein is available in Remington'sPharmaceutical Sciences, 18th Edition. Easton, Pa., Mack PublishingCompany, 1990, the entire contents of which are incorporated byreference herein.

The present compounds are typically administered at a therapeutically orpharmaceutically effective dosage, e.g., a dosage sufficient to providetreatment for tuberculosis. Administration of the compounds orpharmaceutical compositions thereof can be by any method that deliversthe compounds systemically and/or locally. These methods include oralroutes, parenteral routes, intraduodenal routes, and the like.

While human dosage levels have yet to be optimized for the presentcompounds, generally, a daily dose is from about 0.01 to 10.0 mg/kg ofbody weight, for example about 0.1 to 5.0 mg/kg of body weight. Theprecise effective amount will vary from subject to subject and willdepend upon the species, age, the subject's size and health, the natureand extent of the condition being treated, recommendations of thetreating physician, and the therapeutics or combination of therapeuticsselected for administration. The subject may be administered as manydoses as is required to reduce and/or alleviate the signs, symptoms, orcauses of the disease or disorder in question, or bring about any otherdesired alteration of a biological system.

In employing the present compounds for treatment of tuberculosis, anypharmaceutically acceptable mode of administration can be used withother pharmaceutically acceptable excipients, including solid,semi-solid, liquid or aerosol dosage forms, such as, for example,tablets, capsules, powders, liquids, suspensions, suppositories,aerosols or the like. The present compounds can also be administered insustained or controlled release dosage forms, including depotinjections, osmotic pumps, pills, transdermal (includingelectrotransport) patches, and the like, for the prolongedadministration of the compound at a predetermined rate, preferably inunit dosage forms suitable for single administration of precise dosages.

The present compounds may also be administered as compositions preparedas foods for foods or animals, including medical foods, functional food,special nutrition foods and dietary supplements. A “medical food” is aproduct prescribed by a physician that is intended for the specificdietary management of a disorder or health condition for whichdistinctive nutritional requirements exist and may include formulationsfed through a feeding tube (referred to as enteral administration orgavage administration).

A “dietary supplement” shall mean a product that is intended tosupplement the human diet and may be provided in the form of a pill,capsule, tablet, or like formulation. By way of non-limiting example, adietary supplement may include one or more of the following dietaryingredients: vitamins, minerals, herbs, botanicals, amino acids, anddietary substances intended to supplement the diet by increasing totaldietary intake, or a concentrate, metabolite, constituent, extract, orcombinations of these ingredients, not intended as a conventional foodor as the sole item of a meal or diet. Dietary supplements may also beincorporated into foodstuffs, such as functional foods designed topromote control of glucose levels. A “functional food” is an ordinaryfood that has one or more components or ingredients incorporated into itto give a specific medical or physiological benefit, other than a purelynutritional effect. “Special nutrition food”means ingredients designedfor a particular diet related to conditions or to support treatment ofnutritional deficiencies.

Generally, depending on the intended mode of administration, thepharmaceutically acceptable composition will contain about 0.1% to 90%,for example about 0.5% to 50%, by weight of a compound or salt of thepresent compounds, the remainder being suitable pharmaceuticalexcipients, carriers, etc.

One manner of administration for the conditions detailed above is oral,using a convenient daily dosage regimen which can be adjusted accordingto the degree of affliction. For such oral administration, apharmaceutically acceptable, non-toxic composition is formed by theincorporation of any of the normally employed excipients, such as, forexample, mannitol, lactose, starch, magnesium stearate, sodiumsaccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin,sucrose, magnesium carbonate, and the like. Such compositions take theform of solutions, suspensions, tablets, dispersible tablets, pills,capsules, powders, sustained release formulations and the like.

The present compositions may take the form of a pill or tablet and thusthe composition may contain, along with the active ingredient, a diluentsuch as lactose, sucrose, dicalcium phosphate, or the like; a lubricantsuch as magnesium stearate or the like; and a binder such as starch, gumacacia, polyvinylpyrrolidine, gelatin, cellulose and derivativesthereof, and the like.

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, etc. an active compound as definedabove and optional pharmaceutical adjuvants in a carrier, such as, forexample, water, saline, aqueous dextrose, glycerol, glycols, ethanol,and the like, to thereby form a solution or suspension. If desired, thepharmaceutical composition to be administered may also contain minoramounts of nontoxic auxiliary substances such as wetting agents,emulsifying agents, or solubilizing agents, pH buffering agents and thelike, for example, sodium acetate, sodium citrate, cyclodextrinederivatives, sorbitan monolaurate, triethanolamine acetate,triethanolamine oleate, etc.

For oral administration, a pharmaceutically acceptable non-toxiccomposition may be formed by the incorporation of any normally employedexcipients, such as, for example, pharmaceutical grades of mannitol,lactose, starch, magnesium stearate, talcum, cellulose derivatives,sodium croscarmellose, glucose, sucrose, magnesium carbonate, sodiumsaccharin, talcum and the like. Such compositions take the form ofsolutions, suspensions, tablets, capsules, powders, sustained releaseformulations and the like.

For a solid dosage form, a solution or suspension in, for example,propylene carbonate, vegetable oils or triglycerides, may beencapsulated in a gelatin capsule. Such diester solutions, and thepreparation and encapsulation thereof, are disclosed in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545, the contents of each of which areincorporated herein by reference. For a liquid dosage form, thesolution, e.g., in a polyethylene glycol, may be diluted with asufficient quantity of a pharmaceutically acceptable liquid carrier,e.g., water, to be easily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and the like, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells.

Other useful formulations include those set forth in U.S. Pat. Nos. Re.28,819 and 4,358,603, the contents of each of which are herebyincorporated by reference.

Another manner of administration is parenteral administration, generallycharacterized by injection, either subcutaneously, intramuscularly orintravenously. Injectables can be prepared in conventional forms, eitheras liquid solutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. Suitableexcipients are, for example, water, saline, dextrose, glycerol, ethanolor the like. In addition, if desired, the pharmaceutical compositions tobe administered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agents,solubility enhancers, and the like, such as for example, sodium acetate,sorbitan monolaurate, triethanolamine oleate, cyclodextrins, etc.

Another approach for parenteral administration employs the implantationof a slow-release or sustained-release system, such that a constantlevel of dosage is maintained. The percentage of active compoundcontained in such parenteral compositions is highly dependent on thespecific nature thereof, as well as the activity of the compound and theneeds of the subject. However, percentages of active ingredient of 0.01%to 10% in solution are employable and will be higher if the compositionis a solid, which will be subsequently diluted to the above percentages.The composition may comprise 0.2% to 2% of the active agent in solution.

Nasal solutions of the active compound alone or in combination withother pharmaceutically acceptable excipients can also be administered.

Formulations of the active compound or a salt may also be administeredto the respiratory tract as an aerosol or solution for a nebulizer, oras a microfine powder for insufflation, alone or in combination with aninert carrier such as lactose. In such a case, the particles of theformulation have diameters of less than 50 microns, for example lessthan 10 microns.

The present compounds have valuable pharmaceutical properties, whichmake them commercially utilizable. Accordingly, the present subjectmatter further relates to use of the present compounds for the treatmentof diseases such as tuberculosis.

An embodiment of the present subject matter is directed to a method oftreating tuberculosis in a patient, comprising administering to apatient in need thereof a therapeutically effective amount of a compoundas described herein or a pharmaceutically acceptable composition asdescribed herein. A therapeutically effective amount of the compound orpharmaceutically acceptable composition or an amount effective to treata disease, such as tuberculosis, may be determined initially from theExamples described herein and adjusted for specific targeted diseasesusing routine methods.

In an embodiment, the tuberculosis can comprise multiple drug resistant(MDR) strains of Mycobacterium tuberculosis. In another embodiment, thetuberculosis can comprise H37Rv strains of Mycobacterium tuberculosis.In certain embodiments, one or more different forms, strains, or typesof tuberculosis may be treated independently or simultaneously.

Accordingly, in an embodiment of the present subject matter, the presentcompounds as described herein engaged for in vitro study towards H37Rvand multidrug-resistant (MDR) strains of Mycobacterium tuberculosis, candisplay an MIC with a nano to micromolar concentration range. Forexample, a present compound engaged for in vitro study againstsusceptible (H37Rv) strains of Mycobacterium tuberculosis can display anMIC concentration of about 32, about 16, or about 8 μg/mL. For theavoidance of doubt, the present compounds can display an MICconcentration in the range of any two endpoints as described herein.

In another example, a present compound engaged for in vitro studyagainst multidrug-resistant (MDR) strains of Mycobacterium tuberculosiscan display an MIC concentration of about 64, about 32, or about 16μg/mL. For the avoidance of doubt, the present compounds can display anMIC concentration in the range of any two endpoints as described herein.

The present subject matter further relates to a method of treating orpreventing a disease comprising administering to a patient in needthereof a therapeutically effective amount of at least one of thecompounds herein.

In particular, the present subject matter relates to a method oftreating one of the above-mentioned diseases or disorders comprisingadministering to a patient in need thereof a therapeutically effectiveamount of at least one of the compounds herein.

In the above methods, the patient is preferably a mammal, morepreferably a human. Furthermore, in the above methods, at least one ofthe present compounds can be used. In an embodiment, one or two of thepresent compounds are used, or one of the present compounds is used.Similarly, one or more of the present compounds can be used incombination therapy with one or more additional active agents.

The present subject matter can be better understood by referring to thefollowing examples.

EXAMPLES Example 1 Preparation of ethyl 2-substituted-1-(substitutedbenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate analogues (4a-f)

Compounds 4a-4f were synthesized according to the following Scheme 1.

General synthetic procedure for the synthesis of ethyl2-substituted-1-(substitutedbenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylates(4a-f)

To a stirred solution of 6-methylquinoline (1) (2.93 mmol), substitutedphenacyl bromide (2) (2.93 mmol), and K₂CO₃ (5.8 mmol) in 5 mL of DMF,ethyl acetylenecarboxylate (3) (2.93 mmol) was added with stirring. Thereaction mixture was stirred at room temperature for 30 mins. Thecompletion of the reaction was monitored by TLC. The reaction mixturewas evaporated under reduced pressure. The residue obtained wasre-dissolved in ethyl acetate (50 mL), and the ethyl acetate layer waswashed with water (2×10 mL) and brine (1×10 mL) and dried with anhydroussodium sulphate. The organic layer was evaporated under reduced pressureand purified by column chromatography by using 60-120 mesh silica gelwith hexane and ethyl acetate as a eluent to obtain 85-92% of ethyl1-substitutedbenzoyl-7-methylpyrrolo[1,2-a]quinoline-3-carboxylates(4a-f). The physicochemical properties of the title compounds aretabulated in Table 1, above.

The characterization details for the compounds 4a-4f are reported below.

Ethyl 7-methyl-1-(4-methylbenzoyl)pyrrolo[1,2-c]quinoline-3-carboxylate

FT-IR (KBr) cm⁻¹; 3438, 1720, 1527, 1348; ¹H-NMR (CDCl₃, 400 MHz)δ=8.20-8.18 (1H, d, J=9.2 Hz), 7.92-7.90 (2H, d, J=8 Hz), 7.85-7.83 (1H,d, J=8.8 Hz), 7.52-7.47 (3H, m), 7.27-7.25 (3H, m), 4.30-4.25 (2H, q, J=7.2Hz), 2.39 (3H, s), 1.31-1.28 (3H, t, J=7.2 Hz); ¹³C-NMR (CDCl₃, 100MHz) δ=184.84, 164.23, 143.70, 139.88, 135.82, 131.32, 130.34, 130.07,129.21, 128.90, 128.63, 128.35, 128.00, 125.14, 119.95, 117.60, 107.41,60.11, 21.74, 20.96, 14.54; LC-MS (ESI Positive); m/z=(M+H)⁺; 372.2;Anal. Calculated for C₂₄H₂₁NO₃; C, 77.61, H, 5.70, N, 3.77; found; C,77.41, H, 5.60, N, 3.68.

Ethyl 1-benzoyl-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate (4b)

FT-IR (KBr) cm⁻¹; 2970, 1706, 1639, 1537; ¹H-NMR (CDCl₃, 400 MHz)δ=8.23-8.21 (1H, d, J=9.2 Hz), 8.02-8.00 (2H, m), 7.90-7.88 (1H, d, J=8Hz), 7.60-7.54 (3H, m), 7.51-7.46 (3H, m), 7.32-7.29 (1H, m), 4.32-4.26(2H, q, J=7.2 Hz), 2.42 (3H, s), 1.33-1.29 (3H, t, J=7.2 Hz); ¹³C-NMR(CDCl₃, 100 MHz) δ=184.88, 164.17, 140.11, 138.55, 135.29, 132.81,131.35, 130.16, 130.13, 129.45, 128.88, 128.49, 128.37, 127.95, 125.19,120.03, 117.60, 107.57, 60.15, 20.97, 14.53; LC-MS (ESI Positive);m/z=(M+H)⁺; 358.2; Anal. Calculated for C₂₃H₁₉NO₃; C, 77.29, 5.36, N,3.92; found; C, 77.19, H, 5.23, N, 3.87.

Ethyl 1-(4-fluorobenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate

FT-IR (KBr) cm⁻¹; 2977, 1704, 1631, 1596, 1539, 1500, 1423; ¹H-NMR(CDCl₁₃, 400 MHz) δ=8.24-8.21 (1H, d, J=10.2 Hz), 8.06-8.03 (3H, m),7.86-7.83 (1H, d, J=10.2 Hz), 7.57-7.55 (1H, d, J=10.2 Hz), 7.52 (1H,s), 7.32-7.30 (1H, m), 7.18-7.14 (2H, m), 4.33-4.27 (2H, q, J=7.2 Hz),2.42 (3H, s), 1.34-1.30 (3H, t, J=7.2 Hz); ¹³C-NMR (CDCl₃, 100 MHz)δ=183.42, 166.96, 164.44, 164.10, 140.15, 135.37, 134.79, 134.76,132.66, 132.57, 131.28, 130.19, 129.23, 128.97, 128.43, 127.56, 125.19,119.91, 117.60, 115.76, 115.55, 107.64, 60.20, 20.97, 14.53; LC-MS (ESIPositive); m/z=(M+H)⁺; 376.2; Anal. Calculated for C₂₃H₁₈FNO₃; C, 73.59,H, 4.83, N, 3.73; found; C, 73.43, H, 4.82, N, 3.69.

Ethyl 7-methyl-1-(2-nitrobenzoyl)pyrrolo[1,2-a]quinoline-3-carboxylate

FT-IR (KBr) cm⁻¹; 2921, 1693, 1641, 1525, 1502, 1352; ¹H-NMR (CDCl₃, 400MHz) δ=8.50-8.48 (1H, d, J=8.8 Hz), 8.16-8.10 (2H, m), 7.74-7.72 (1H,m), 7.65-7.57 (3H, m), 7.49 (1H, s), 7.45-7.43 (1H, m), 7.18 (1H, s),4.27-4.22 (2H, q, J=7.2 Hz), 2.43 (3H, s), 1.29-1.25 (3H, t, J=7.2 Hz);¹³C-NMR (CDCl₃, 100 MHz) δ=181.20, 163.79, 162.68, 147.44, 140.93,136.38, 135.79, 133.98, 131.76, 131.01, 130.47, 130.27, 129.95, 128.90,128.03, 125.29, 124.56, 120.52, 117.31, 107.88, 60.30, 21.01, 14.48;LC-MS (ESI Positive); m/z=(M+H)³⁰ ; 403.2; Anal. Calculated forC₂₃H₁₈N₂O₅; C, 68.65, H, 4.51, N, 6.96; found; C, 68.46, H, 4.38, N,6.79.

Ethyl 1-(4-bromobenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4e)

FT-IR (KBr) cm⁻¹; 2970, 1699, 1629, 1461, 1421; ¹H-NMR (CDCl³, 400 MHz)δ=8.24-8.22 (1H, d, J=9.2 Hz), 7.90-7.87 (3H, m), 7.64-7.52 (5H, m),7.33-7.30 (1H, m), 4.32-4.27 (2H, q, J=7.2 Hz), 2.42 (3H, s), 1.34-1.30(3H, t, J=7.2 Hz); ¹³C-NMR (CDCl₃, 100 MHz) δ=183.56, 164.03, 140.33,137.37, 135.45, 131.80, 131.59, 131.29, 130.23, 129.55, 129.15, 128.44,127.85, 127.47, 125.22, 119.95, 117.56, 107.76, 60.22, 14.53; LC-MS (ESIPositive); m/z=(M+H)⁺; 436.2; Anal. Calculated for C₂₃H₁₈BrNO₃; C,63.32, H, 4.16, N, 3.21; found; C, 63.19, H, 4.09, N, 3.07.

Ethyl 1-(3,5-bis(trifluoromethyl)benzoyl)-7-methylpyrrolo[1,2-c]quinoline-3-carboxylate (4f)

FT-IR (KBr) cm⁻¹; 2985, 1718, 1637, 1539, 1502, 1460, 1425; ¹H-NMR(CDCl₃, 400 MHz) δ 8.43 (2H, s), 8.26-8.24 (1H, d, J=9.2 Hz), 8.07 (1H,s), 7.94 (1H, s), 7.90-7.87 (1H, d, J=8.8 Hz), 7.64-7.62 (1H, d, J=8.8Hz), 7.51 (1H, s), 7.36-7.33 (1H, m), 4.30-4.25 (2H, q, J=7.2 Hz), 2.39(3H, s), 1.31-1.28 (3H, t, J=7.2Hz); 13 C-NMR (CDCl₃, 100 MHz) δ=180.96,163.69, 162.67, 141.00, 140.75, 135.86, 132.31, 131.97, 131.25, 130.45,130.05, 129.82, 128.58, 126.66, 125.85, 125.29, 119.92, 117.46, 108.51,60.39, 36.53, 20.98, 14.46; LC-MS (ESI Positive); m/z=(M+H)⁺; 494.2;Anal. Calculated for C₂₅H₁₇F₆NO₃; C, 60.86, H, 3.47, N, 2.84; found; C,60.71, H, 3.39, N, 2.79.

Example 2 Anti-tubercular Activity

The anti-tubercular activity of the designed compounds 4a-f wereevaluated

against two types of MTB strains, namely H37Rv and well characterisedMDR strains using the colorimetric Resazurin Microplate Assay (REMA)method. A 100 mL of Middlebrook 7H9 broth was aseptically prepared anddispensed in each of the wells of a 96 well flat-bottomed microtiterplate with lids (Lasec, South Africa). Each of the test compounds wasaccurately weighed, dissolved in the appropriate solvent, and filtersterilised using a 0.2 micron polycarbonate filter. Stock solutions ofthe test samples were aliquoted into cryovials and stored at −20° C. A100 mL of the test samples were added to each of the wells containingMiddlebrook 7H9 broth supplemented with 0.1% Casitone, 0.5% glycerol,and 10% OADC (oleic acid, albumin, dextrose, and catalase). The testsamples were then serially diluted two folds directly in the broth ofthe microtiter plate to the desired concentration ranging from 40-0.625mg/mL. Inoculums from clinical isolates were prepared fresh fromMiddlebrook 7H11 agar plates by scraping and re-suspending loopful ofcolonies into Middlebrook 7H9 broth containing glass beads. The inoculumturbidity was adjusted to a McFarland number 1 standard and furtherdiluted to 1:10 in M7H9 broth prior to the addition of 100 mL to each ofthe test samples and drug-free wells. Growth control and a sterilecontrol were also included for each isolate. Sterile M7H9 broth wasadded to all perimeter walls to avoid evaporation during the incubation.The plate was covered, sealed in a plastic bag, and incubated at 37° C.After 8 days of incubation, 30 mL of 0.02% working solution of resazurinsalt was inoculated into each microtiter well. The plates were thenincubated overnight and read the following day. A positive reactionresulted in a colour change from blue to pink owing to the reduction ofresazurin to rezarufin which confirmed MTB cell viability/growth and,hence, drug resistance. The MICs were defined as the minimum drugconcentration to inhibit the growth of the organism with no colourchanges present in the well. The observed anti-tubercular activity ofthe present ethyl2-substituted-1-(substitutedbenzoyl)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylates(4a-f) derivatives against H37Rv and multidrug-resistant (MDR) strainsof Mycobacterium tuberculosis are summarized below in Table 2.

TABLE 2 Compound MIC (μg/mL) code Susceptible (H37Rv)* MDR Strain** 4d 816 4e 32 32 4f 16 64 MIC, minimum inhibitory concentration *AmericanType Culture Collection (ATCC): 25177. **These isolates are resistant tofirst-line antibiotics isoniazid (0.2 μg/mL) and rifampicin (1 μg/mL).

It is to be understood that the present compounds, compositions, andmethods are not limited to the specific embodiments described above, butencompasses any and all embodiments within the scope of the genericlanguage of the following claims enabled by the embodiments describedherein, or otherwise shown in the drawings or described above in termssufficient to enable one of ordinary skill in the art to make and usethe claimed subject matter.

We claim:
 1. A compound having the formula I: . . .

or a pharmaceutically acceptable salt, ester, stereoisomer, or solvatethereof, wherein: R is selected from the group consisting of methyl,fluorine, and trifluoromethyl; n is 1 or 2; and provided that when n is1, R is not 4-fluorine.
 2. The compound of claim 1, wherein R and n,when taken together, can be selected from the group consisting of4-methyl, and 3,5-CF₃.
 3. The compound of claim 1, wherein the compoundis selected from the group consisting of: Ethyl7-methyl-1-(4-methylbenzoyl)pyrrolo[1,2-a]quinoline-3-carboxylate (4a);Ethyl1-(3,5-bis(trifluoromethyl)benzoyI)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4f); and a pharmaceutically acceptable salt, ester, stereoisomer, orsolvate thereof.
 4. A pharmaceutical composition comprising the compoundof claim 1 and a pharmaceutically acceptable carrier.
 5. A compoundhaving the formula I:

or a pharmaceutically acceptable salt, ester, stereoisomer, or solvatethereof, wherein: R and n taken together and are selected from the groupconsisting of 4-methyl, and 3,5-CF₃.
 6. A pharmaceutical compositioncomprising the compound of claim 5 and a pharmaceutically acceptablecarrier.
 7. The compound of claim 5, wherein the compound is selectedfrom the group consisting of: Ethyl7-methyl-1-(4-methylbenzoyl)pyrrolo[1,2-a]quinoline-3-carboxylate (4a);Ethyl1-(3,5-bis(trifluoromethyl)benzoyI)-7-methylpyrrolo[1,2-a]quinoline-3-carboxylate(4f); and a pharmaceutically acceptable salt, ester, stereoisomer, orsolvate thereof.
 8. A pharmaceutical composition comprising the compoundof claim 7 and a pharmaceutically acceptable carrier.